Despite remarkable efforts provided in biology, virology and drug research including molecular modeling during the first decade after the initial description of AIDS in 1981, two drugs only, e.g. 3'-azido-2',3'-deoxythymidine (AZT, Retrovir, Zidovudine) and 2',3'-dideoxyadenosine (Didanosine, Videx) are approved for the treatment of AIDS patients and AIDS-related complex (ARC) as referenced by Mitsuya, H. et al., Proc. Natl. Acad. Sci., USA, 1985, 82, 7096-70100; Mitsuya, H., & Broder, S., Proc. Natl. Acad. Sci., USA, 1986, 83, 1911-1915). Both compounds are 2',3'-dideoxynucleoside analogues and most widely used as antiviral (retroviral) agent in both single and combination strategies for the treatment of acquired immunodeficiency syndrome (AIDS). Both compounds must be phosphorylated intracellularly to their 5'-triphosphate derivatives to interact with their target enzyme, the HIV-associated reverse transcriptase (RT). At the RT-level, the dideoxynucleoside triphosphates (dNTPs) can act as either competitive inhibitors preventing the incorporation of the natural substrates (dNTPs) or alternate substrates incorporated into the growing DNA chain. Furthermore, their incorporation leads to termination of the DNA chain since they do not process the 3'-hydroxy necessary for chain elongation. Another principle mode of infection by the human immunodeficiency virus of types, e.g. 1 and 2 (HIV-1 & HIV-2) involves the interaction of the HIV envelope protein gp 120 with CD4, a molecule on host lymphoid cells (see Ne .g. Dalgeish et al., Nature, 1984, 312, 763; Jameson, B. A., et al., Science, 1988, 240, 1335; Collman,R., et al., J. Virol., 1990, 64, 4468). Moreover, the susceptibility of many CD4 negative cell lines to HIV infection, however, suggests the presence of an alternative entry pathway according to e g. Clapham, P. R., et al., Nature, 1989, 337, 368; McKeating, J. A., et al., Nature, 1990, 343, 659. Other key factors regulating replication of the HIV are, apart from the RT with the three recognized enzymatic activities, i.e. the RNA dependent polymerase, DNA-dependent polymerase and the ribonuclease H, are the protease (PR) and the integrase, which are also essential for replication. The design of potent and structurally diverse HIV PR inhibitors has emerged over the past few years and has exemplified varying chemical templates, stereochemical complexity and molecular recognition properties in binding to the target enzyme, resulting in a clinically effective HIV-PR-inhibitor (see Thaisrivongs, S., Report Med. Chem., 1994, 29, 133 and references therein; Chang, H. E. J., Physicians Assoc. AIDS Care, 1994, and references therein). Also avenues for the treatment of HIV infection other than RT and PR inhibition have become evident over the last years. Plant alkaloids which modify the glycosylation of gp 120 inhibit the infectivity of HIV (Tyms, A. S. et al., Lancet, 1987, 11, 1025; Walker, B. D., et al., Proc. Natl. Acad. Sci., USA, 1987, 84, 8120) as well as castanospermine which is believed to excert its antiviral effect by reduction in virus infectivity and reduction in cell-to cell spread of the virus by inhibition of cell fusion events.
Very recently, Grundmann & Rubsamen-Weigmann reported in their patent, EP 0 516 660 B1 (1993), entitled "Use of S-adenosylmethionine as an agent against infections by retroviruses", an in-vitro inhibition of RT with notably inhibiting concentrations of approximately 100-200 .mu.g/mL of S-adenosylmethionine (SAM) when administered as the tosylate-bis-sulfate salt applying lymphocyte cell cultures prepared from the umbilical cord of newborns. These lymphocyte cultures were inoculated with HIV taken from blood of an AIDS patient. The disclosed inhibitory concentrations of SAM is meant as the apparent concentration of SAM, which inhibits under their in vitro assay conditions 50% of the RT activity. Recalculations of the inhibitory effect of SAM on their RT would led us to an apparent K.sub.i value of approx. 200-250 nM after suitable corrections for the presence of dithiothreitol, DTT, which have to be applied. Inhibitory experiments using DTT, e g. for protecting sulfhydryl groups of the enzyme (RT), in their assay have to be omitted or corrected for, respectively, since DTT act as a strong reducing agent, particularly for SAM or SAM-tosylate-bis-sulfate which potentiates the reduction due to the sulfonium group which is being reduced to the sulfinium group, or to S-S-complexes comprising of SAM and DDT, respectively. Therefore, the apparent efficient inhibitory concentrations of SAM can well be lower than the measured ones. Note, the determined inhibitory concentrations are not the ones which can be correlated to the ones according to Michaelis-Menten kinetics. At least similar findings with respect to treatment of AIDS-patients revealing strong neurological disorder due to HIV-infection are disclosed in the European Patent Application 0 482 493 A2 by Bioresearch S.p.A. However, their study selected SAM and a derivative of tetrahydro-folic acid as the pharmaceutical ingredient administered a dose of 500 mg/kg/day parenteral including 0.5-1.0 mg/kg/day 5-methyl-tetrahydro-folic acid as a supplement. Basically this disclosure is concerned with the AIDS-induced neurological disorders in patients without addressing the importance of action of SAM on the RT as shown previously by Grundmann & Rubsamen-Weigmann. This view is endorsed through experiments conducted with 5-fluoro-deoxy uridylate (F-dUP) or the corresponding nucleoside, respectively, which is known as a powerful inhibitor of the thymidilate synthetase which uses a methyl group from a tetrahydrofolate species to synthesize TMP. In applying the in vitro assay for inhibition of RT in the presence or absence of F-dUP or F-dU the same K.sub.i value for SAM is obtained as determined by Grundmann & Rubsamen-Weigmann. This is a strong support that F-dU has no influence on the inhibition of RT, also no significant inhibition of the RT has been detected in the presence of 5,6,7,8-tetrahydropteridine (THF), a constituent of folinic acid or N.sup.5, N.sup.10 -methylene-6-[.sup.3 H]-THF with the RT enzymes. This establishes clearly the mode of action of SAM on the RT in an inhibitory sense which the Bioresearch Patent failed to disclose since the above mentioned experiments reveal no involvement of THF in the inhibition of RT.
As outlined above there are several drugs that have shown to be potent for the treatment of HIV infection. But, as it is known for e g. AZT, any of these drugs have serious dose-limiting toxicities, and most importantly HIV develops resistance against these drugs after a certain period of time (see e g. Richman, D. D. et al., Acquired Immune Defic. Syndr. 7,189, 1994; Richman, D. D., Antimicrob. Agents. Chemother., 37, 1207, 1993; Montanier, L. S., et al. AIDS 7, 189, 1993. Furthermore, in light of the limited benefits when HIV infected patients were treated with anti-retroviral compounds, the likely causes of these limited benefits are possibly the emergence of drug resistant strains during monotherapy. The potential use and mechanism for sustained anti-retroviral efficacy is documented for example very recently for the AZT-3TC combination therapy (3TC=[-]-2'-deoxy-3'-thiacytidine) according to Larder, Kemp & Harrigan (Science 269, 696-699, 1995). These authors showed that an AZT-3TC combination therapy resulted in a markedly greater decrease in serum HIV-1 RNA concentrations than treatment with AZT alone, even though valine-184 mutants rapidly emerged. In addition, AZT-3TC coresistance was not observed during extensive in vitro selection with both compounds.